Immunosenescence, or the decline in immune function with age, results in a reduced ability of elderly patients to effectively detect and fight infections. Respiratory tract infections (RTIs), the majority of which are caused by viruses, are a leading cause of death in the elderly, and few therapies exist to treat them. Inhibition of the mechanistic Target of Rapamycin (mTOR) pathway has been shown to extend lifespan and ameliorate multiple aging-related pathologies including immunosenescence. mTOR functions as part of at least two multi-protein complexes, TORC1 and TORC2. TORC1 inhibition has been shown to ameliorate immunosenesence in both preclinical models and clinical studies, including two Phase 2a studies in almost 500 elderly subjects. At doses that selectively inhibit TORC1, the small-molecule drugs BEZ235 and RAD001 enhanced vaccination response and reduced infections, including RTIs, in elderly subjects. Importantly, these beneficial effects were accompanied by an increase in blood antiviral interferon stimulated gene (ISG) expression. Based on these findings, we hypothesize that basal innate antiviral gene expression is deficient in the elderly, and that TORC1 inhibitors upregulate antiviral gene expression in blood and respiratory tract epithelium in the elderly and thereby reduce the incidence of RTIs. We will leverage our ongoing and planned clinical trials of these drugs to test the hypothesis that TORC1 inhibition reduces the incidence of RTIs in elderly subjects by upregulating antiviral ISG expression. Specifically, we will measure the extent and kinetics of blood and pharyngeal ISG upregulation following TORC1 inhibitor administration and examine the relationship between ISG expression upregulation, TORC1 inhibitor exposure, and RTI incidence. We further propose to determine the mechanism by which TORC1 inhibitors upregulate ISG expression using an in vitro influenza infection model. We will use this model to investigate potential nodes within the interferon-signaling pathway that mediate the upregulation of ISG expression and antiviral effects of TORC1 inhibitors. Finally, we will determine if populations known to be at risk of RTI-related morbidity and mortality have deficient ISG expression by comparing baseline ISG expression in blood and nasopharyngeal swabs between young and elderly subjects, and between subjects of both age groups with and without COPD and asthma. We expect that the proposed work will provide important insights into the mechanism by which TORC1 inhibitors improve immune function and decrease infection rates in the elderly. Moreover, broadening our understanding of the mechanism underlying the immune enhancing effects of TORC1 inhibitors will help define new targets to exploit for treatment of immunosenescence.